PAK1 Regulates Inhibitory Synaptic Transmission Through Endocannabinoid Signaling

PAK1 is a serine/threoine kinase,plays an important role on manipulating neural function through regulating cytoskeleton and gene expression.It was reported that inhibition of PAK1 can improve social and cognitive function in multiple mouse models of autism,but the underlying mechanisms remain unclear.These animal models showed common phenotypes like unbalance of neural excitation and inhibition,abnormal endocannabinoid signaling.Here,transgenic mice,protein inhibitors and protein inhibitory peptides were used to study the mechanism of PAK1’s function on regulating synaptic transmission.Our data showed that disruption of PAK1 can:1,depress inhibitory synaptic transmission and increase excitatory/inhibitory(E/I)ratio;2,decrease inhibitory synaptic COX-2 distribution,and upregulate tonic endocannabinoid(eCB),which is anandamide(AEA);3,rescue social memory deficits in fmr1 knock out mice,which is dependent on CB1R.A new signaling pathway PAK1-COX-2-AEA-CB1R was identified here,which contribute to maintaining normal inhibitory synaptic transmission and E/I balance.It can rescue autistic behavior through manipulating this signaling pathway.PAK1 and eCB are both involved in many other organ systems in addition to brain of mamalian,this finding may also provide a new mechanism for these system’s functions and dysfunctions,including inflammations and cancer.